Department of Gastroenterology, Nantong University Affiliated Hospital, Nantong, Jiangsu, China.
State Key Laboratory of Cell Biology, CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Cancer Res. 2019 Sep 1;79(17):4387-4398. doi: 10.1158/0008-5472.CAN-18-4032. Epub 2019 Jul 9.
Gastric cancer is the third leading cause of cancer-related death worldwide. The regulatory mechanisms underlying gastric cancer cell proliferation are largely unclear. Here, we show that the transcription factor GFI1 is associated with advanced clinical gastric cancer progression and promoted gastric cancer cell proliferation partially through inhibition of gastrokine-2 (GKN2) transcription. GFI1 was a degrading substrate of FBXW7, whose loss was observed in gastric cancer. Mechanistically, GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. A nondegradable GFI1 S94A/S98A mutant was more potent in driving gastric cancer cell proliferation and tumorigenesis than wild-type GFI1. Overall, this study reveals the oncogenic role of GFI1 in gastric cancer and provides mechanistic insights into the tumor suppressor function of FBXW7. SIGNIFICANCE: These findings demonstrate the oncogenic role of the transcription factor GFI1 and the tumor suppressive function of FBXW7 in gastric cancer.
胃癌是全球癌症相关死亡的第三大主要原因。胃癌细胞增殖的调节机制在很大程度上尚不清楚。在这里，我们表明转录因子 GFI1 与晚期临床胃癌进展相关，并通过部分抑制胃泌素-2（GKN2）转录来促进胃癌细胞增殖。GFI1 是 FBXW7 的降解底物，在胃癌中观察到 FBXW7 的缺失。在机制上，GSK3β 介导的 GFI1 S94/S98 磷酸化触发其与 FBXW7 的相互作用，导致 SCFFBXW7 介导的泛素化和降解。与野生型 GFI1 相比，驱动胃癌细胞增殖和肿瘤发生的非降解性 GFI1 S94A/S98A 突变体更有效。总的来说，这项研究揭示了 GFI1 在胃癌中的致癌作用，并为 FBXW7 的肿瘤抑制功能提供了机制上的见解。
这些发现表明转录因子 GFI1 具有致癌作用，FBXW7 在胃癌中具有肿瘤抑制功能。
